Posted
by
Soulskill
on Wednesday October 08, 2014 @11:04AM
from the do-you-feel-lucky,-punk? dept.

An anonymous reader writes: Medical researchers hope an experimental vaccine for Ebola can help protect against infection and slow the spread of the disease. Efficacy trials for the vaccine begin in a few months, and it's forcing some difficult decisions for health care officials. The first test will involve front line health care workers, who, as a group, are at the gravest risk of infection. But every trial needs a control group, and scientists are bitterly divided over whether the vaccine should be withheld from a portion of those putting their lives on the line to protect the rest of us. Development of the vaccine has been vastly accelerated already, due to the virus's spread and its mortality rate.

"The leading alternative is a design known as step-wedge, which essentially uses time to create a control group. In this design, researchers take advantage of the inescapable reality that large-scale trials can't give everyone the vaccine on the exact same date; they compare the rates of infection in people already vaccinated with those who have yet to receive the shots. Barney Graham, a virologist ... says "people are more comfortable" with the step-wedge design, because everyone in such a study would get the Ebola vaccine. But statistically speaking, this design makes it more difficult to determine the vaccine's worth, and it takes longer." NY Mag has a related story summarizing the treatments currently being used to fight Ebola.

The difficulty in determining the effectiveness of the vaccine when you give it to everyone is dependant on how effective it is. If it reduces the chances of exposure resulting in infection by 10%, then yes, it will be tough to show that it's not useless. However, if it reduces the chances by 90%, it will be quite obvious.

A complicating factor is that, for most vaccination systems, the person will always in future test positive for antibodies to the virus. So, if you vaccinate someone, and some weeks/ months/ years/ decades later they report symptoms not incompatible with Ebola, then you have no way of finding out if they have Ebola, other than waiting for the disease to progress.

Same for whatever other disease you're vaccinating against. We had this debate ad nauseam in 2001, during the FMD outbreak [wikipedia.org]. That litle point of vi

"Development of the vaccine has been vastly accelerated already, due to the virus's spread and its mortality rate." Ebola isn't new. What's new is that there's now a very real chance of the infection spreading to countries where white people live. Hence the "vastly accelerated" development.

I don't think that this may fool the health workers, many of whom may remember the polio vaccine as "dead poliovirus that is proved to make you immune to live polio".
Among those who are not in the health industry, "hopefully dead Ebola virus that we think might make you immune to live Ebola" is almost indistinguishable from "we think that dead Ebola virus might hopefully make you immune to live Ebola," which will be enough to make people feel deceived if they believe to have had the real shot, while havin

Your study is doomed already. Ask the researchers that tested AIDs drugs in the 80s. People will share pills in an attempt to be sure they got the right thing. They'll buy them on the black market. They'll join multiple studies and take herbal remedies. When death is on the line people will do what they need to do to survive, your study be damned. So just give the drug to them all and save your study work for when there isn't an epidemic going on.

When death is on the line people will do what they need to do to survive, your study be damned.

They'll do what they THINK will help even if there is no evidence to back that up. Just because desperate people are being (understandably) irrational doesn't mean the rest of us should join them. We do things the way we do them because it works and because the alternatives result in much worse problems [wikipedia.org].

So just give the drug to them all and save your study work for when there isn't an epidemic going on.

There is always an epidemic going on somewhere. The value of these studies is that it saves many at the expense of a few. That is the cold hard fact of medicine. Some people are going to die/suffer so

The point is... while this epidemic is going on, it will be very hard to control the study. Most Ebola outbreaks affect less than a few hundred people. There are enough people in Africa infected now that if you limit access to this Vaccine a whole cottage industry will likely spring up around it. Just like it did over AZT in the 80s. Do YOU want to be the healthcare worker guarding the stash of drugs that's the only hope for survival to the teaming throngs surrounding your clinic?

Give it to everyone, hope for the best, when the worst is over start your study.

Of course, if the experimental vaccine is effective, then we should be keeping people from dying and we don't need a control group. But this is an unwarranted assumption: we don't know yet if the exerimental vaccine is effective -- this is what we are trying to determine, and we won't have the answer until after the experiment.

You say "we already know the death rate of ebola through empirical observation", but the death rate depends on many variables. For example, health-care workers probably have better

Safe and effective are both important questions. Which is why you test both questions at the same time, along with other questions (dose, administration route, adjuvants). And of course, you want to get all the answers to these questions as soon as possible, and to kill as few people as possible.

The only objective is to keep them from dying, and we already know the death rate of ebola through empirical observation, so we don't need a control group.

I disagree strongly with your framing of this issue. The objective is (or should be) to keep the LARGEST POSSIBLE number of people from dying. This means that we have to weigh the needs of the patients who are sick right now against the needs of future patients who will become infected. The demonstrated best way to learn if a treatment is effective, safe and to learn why is through controlled studies. Often this means we sacrifice some so that more may live in the future. While i'm not suggesting we do

Well said. You also want to know if your vaccine causes a recipient to contract rapid onset brain cancer, or some other side effect that might be just as bad as the thing that you are trying to prevent/cure in the first place before you administer it to everyone. The Hippocratic oath contains a line about 'Do no harm'.

Controls save lives, because they allow you to work with less data and reach a conclusion more quickly. Note that even controlled experiments are never conclusive, but without controls you need much, much more data to make a compelling case for efficacy.

Bullshit. The vaccine is not finished in the trials, a lot of optimization still needs to be done at that stage. Also, it would not be the first time that the side-effects are worse than the benefits on first trials. In order to get a handle on that, accurate effectiveness numbers and accurate estimates of side-effects are urgently needed. This process cannot be short-circuited without dire consequences.

Using the population (of infected people) as a control group. Say you have two potential vaccines, A and B (this could even be different dosages of the same vaccine, or different adjuvants at the same dosage, or oral vaccine versus injected). Your population mortality is 65% +/- 5% (because you do not know everyone infected, or everyone who dies) and your two candidate vaccines have mortality rates of 55% +/-15% (smaller sample size leads to higher uncertainty) and 52% +/-20% respectively.

One problem with rushing a treatment to market (aside from the obvious side effects and toxicity risks) is that you sometimes end up with a treatment that works but you have no idea why it works. This has happened with some drugs in the past. We've started testing them and found that they worked really well. So we stopped the clinical trials early in order to rush the drug to market quickly for perfectly appropriate humanitarian reasons. After all if you have a drug that you know works then it's pretty cruel to withhold it from someone who would benefit. The problem is that sometimes we know a drug works before we know why or how it works.

Part of clinical trials is figuring out if a treatment will work. The other part which is sometimes even more important is figuring out why a treatment works so that we can build off that information in the future. If you skip or stop clinical trials early you sometimes end up losing this critical information. If we don't know why something works it's pretty hard to make further progress in developing even better treatments.

You can always do that research in the future. Rushing a life-saving treatment to deployment is always ethical: people like to bitch about experimentation on humans and all the complications and side-effects and suffering you can cause, but this doesn't fucking apply when your human guinnea pigs are definitely going to die soon. If you can make them not die, failure is a null outcome.

So lives in the future are worth less than lives now? I could not disagree more. If we practiced what you suggest we would never do any studies because we would always be putting them off into the future. We use controlled studies because it is the best way to know if something works and just as importantly why it works. And yes this comes at the cost of some lives. We sacrifice some so that more may live in the future. If you can find a better way to do it then let us know and go collect your Nobel p

Well, if you have a terminal cancer patient, and you give them no treatment, they die. If you give them a treatment and it doesn't work, they die. If the treatment has horrible side effects, you could give them a suicide pill. Or maybe the treatment just works.

It's "unethical" to experiment on humans, and "ethical" to make ourselves feel good by simply staring at them and telling them to die so they will have the dignity of not being a human guinea pig. Which is stupid: it's unethical to withhold pot

We can show that the vaccine is safe already. Besides, if more people die when on the vaccine, it's probably because of the vaccine.

You're also using an undistributed middle fallacy: vaccines prevent contraction of the disease. Death rate is a consequence of contracting the disease. In the population, 16% may die: 80% fatality from Ebola, 20% transmission rate. A vaccine would drop the transmission rate--maybe 10% transmission rate, and 8% of the population dies.

Statistics works better if you gather lots of data. For HIV, cancer, and ebola, you can gather more statistical data over time even without doing direct controlled studies. You can also compare those to animal models. You can keep cracking on the problem of why and to what degree. In other words: you can better control the experiment in a future setting, and possibly reduce risk to humans.

We have reason to believe the treatment will work. We also have reason to believe they're safer than death (we have reason to believe they're reasonably harmless in their own right, but that's extreme compared to the benchmark of preventing death). Thus your statement is both misleading (not entirely inaccurate) and irrelevant.

Not true. That's the point -- more statistical data is useless if you're not collecting it in a way that will give you an answer. The only way to get an answer is with a randomized, controlled trial. Animals aren't humans.

I see you've done no real statistics or explored any real science.

Many mechanisms of actions for many modern drugs are explained by animal models. For example: anything that

We have reason to believe the treatment will work. We also have reason to believe they're safer than death (we have reason to believe they're reasonably harmless in their own right, but that's extreme compared to the benchmark of preventing death). Thus your statement is both misleading (not entirely inaccurate) and irrelevant.

Personally, I could accept giving drugs from Phase II trials to informed patients if the only costs were the financial costs, and the risks of adverse effects. But the real danger is that the medical community goes off in all different directions, without a strategy, and winds up with data that doesn't give them the information they need.

It's moot, because the costs to a drug company of giving individualized premarket drugs to patients is enormous, and they don't usually have drugs available for compassiona

Well, gee, I read half a dozen clinical studies in the major medical journals every week and write reports on them. My boss seems to think I understand them OK. And I go to conferences where I meet the investigators and talk to them, to make sure I got it right.

If, like them, you have a PhD or MD and work in drug development, I'll give your opinions appropriate weight. Although I think it's commendable when a layman tries to learn more about medicine and science.

Short version: You've read some medical papers, which make use of statistics in experiments. I've been told I'm the only person in history to get a perfect score on the advanced placement statistics and probability exam, although I'm sure that was just the excited babble of an obsessive asian math teacher. I do have a founding grasp on statistical analysis, experimental design, and the complexities and shortcomings of studies over experiments.

You got me there. I can't make any sense out of that paragraph at all. Maybe I don't know what I"m talking about.

To illustrate, let's assume that Africans are terrible at running medical facilities and experience a 75% transmission rate per week: 3/4 of their healthcare providers in Ebola treatment facilities contract ebola EVERY WEEK. European facilities with similar load experience a 1% transmission rate. If your drug is 50% effective, you should immediately see a 37.5% drop in Ebola transmission in African facilities; in European facilities, you'll see a 0.5% drop.

Your assumptions are all wrong.

First, there is no ethics committee in the world that would allow western scientists to go to African clinics to perform such an experiment and not give them help in cutting their Ebola transmission. You're describing the Tuskegee syphilis study. Gowns, gloves and standard procedures would reduce transmission more than a vaccine.

Second, people used to do studies like you describe and they didn't produce reliable results. Drug companies used to do studies like that and still do

Your arguments are silly. My way is a known, standard, valid statistical method; it's not my fault some people mis-apply them to falsify information. I can do randomized, controlled tests and produce a variety of results based on analysis. This has been done for everything from hospital survival rates to psychological studies.

It's been shown, for example, that you can take two hospitals with inpatient and outpatient surgeries and show that either is statistically more survivable. One hospital may sho

The solution to this is easy, it's just ones America's puritan's can't swallow. You send over terminally ill volunteers who have a short time to live anyways. You use them as the non-vaccinated group. If they contract Ebola, you allow them an assisted death (OH THE HORROR/THINK OF BABY JESUS). Everyone wins.

The solution to this is easy, it's just ones America's puritan's can't swallow. You send over terminally ill volunteers who have a short time to live anyways. You use them as the non-vaccinated group. If they contract Ebola, you allow them an assisted death (OH THE HORROR/THINK OF BABY JESUS). Everyone wins.

So your control group consists of people in poor health and weak immune systems?

Any experimental intervension will look effective against that control.

Because every terminal illness causes a weakened immune system, right? If you're diagnosed with a brain tumor and given six months to live, you're likely still healthy, and your immune system is fully functioning. We aren't talking about sending full blown AIDS patients as a test group...

Any time someone says strong or weak with regard to the immune system, it's a good clue that don't actually know what they are talking about.

And yes, people who are ill for ANY REASON have a change in their immune response.In your example(brain tumor), Immune cells cause the FasL to commit suicide. Sadly, the FasL proteins are created faster then the immune response can handle. If they can get the gliomas to slow down or stop the expression of the FasL protein, the immune system would take care of the tum

1. I guess you should tell that to OP then, I was responding with terminology he chose. I just chose not to respond like a condescending douche. You should try it sometime.
2. No, that's not what causes a brain tumor. I'm glad you managed to garner some buzz words in your second year biology course, but you might want to crack that book back open.

I never claimed to "know so much about" the immune system. I guess your reading comprehension issues still persist. Now shoo troll, nobody cares.

Sure, it is tough, but without the control group all scientific basis for efficiency evaluation goes out the window. That leads to guesswork that routinely kills a lot more people later. That said, of course the control group should be as small as possible as it can be and still give scientifically sound results. It might also be a good idea to give the members or the control group preferential treatment when they get infected to offset the higher risk they are running. But there is no way to get around th

They are doing more about it because of the scale of the current problem.
That scale is also the reason a person in the US got infected.
The scale is likely the result of a mutation in the virus, there's a much longer incubation time now.

A clarification; No person in the US has gotten infected, as far as I know. The only US cases are those infected outside the US and then traveling to the US. There was a nurse in Spain that got infected from a patient, otherwise I don't think there are any known infections that happened outside of Africa.

The scale is likely the result of a mutation in the virus, there's a much longer incubation time now.

I'm not aware of any evidence of a particular mutation that has been identified leading to this putative increase in incubation period. The observed differences in incubation rates estimated for this outbreak are not different enough to point to a different incubation period, when you take into account that the statistics being collected are sample statistics, not population statistics. Not everyone who dies

No, the rush to create a vaccine coinicdes with the latest outbreak, which has 10 times (and counting) the number of infected as the next largest outbreak. More importantly, all previous outbreaks were local and contained reasonably easily. This is the first time Ebola is getting away from us; in previous cases we had the option of containing it and letting it run its course, now it looks like that may no longer be enough.

And before this outbreak happened, research into vaccines was already taking place. Of course the urgency is somewhat higher now, since we may be looking at a global epidemic. This has nothing to do with ohmygodanAMERICANgotinfected.

This latest outbreak has already infected more than in the entire history of the virus prior to it. There hasn't been a great deal of effort, because there simply hasn't been a great deal of need. It takes time for labs to spool up against an outbreak, and the fact that new treatments are coming down the pipeline right around the same time the virus starts spreading to other countries is purely coincidence.

What vaccine? There is no vaccine? All we have is antiviral drugs that are effectively antibody supplements. In previous outbreaks, people have been cured by receiving blood (and antibodies) from someone who has already successfully fought off the infection. The drugs are basically just an artificially manufactured form of that. You don't run large volume production of an experimental drug for a virus that only has small outbreaks every few years.

That article cites a vaccine from GlaxoSmithKline that started human trials on September 2nd, and also mentioned the Public Health Agency of Canada vaccine. These aren't hypothetical. They are untested, but not hypothetical.

Funny that ebola has been in existence in the modern world since the 70s, yet only now this is coming to light. Oddly enough, this is perfectly timed with someone in the US getting infected.

"Shit, this is on OUR turf now!??! Better do something about it!"

There is a causal relation driving this correlation, but it's not the one you cynically postulate. Both the appearance of someone in the US with the disease and the attempt to create a vaccine have been caused by the scale of the latest outbreak.

All these snarky comments do highlight a point though (which I am sure will offend many): Why should any non-African nation even have to do anything-Ebola related ever?

Because diseases don't respect borders, and people move around.

I live in Britain ; next month I'm likely to be working in Canada ; last month I was working in West Africa. There are approximately 80 Americans working on the same vessel as me, commuting month-by-month to the USA.

Funny that ebola has been in existence in the modern world since the 70s, yet only now this is coming to light. Oddly enough, this is perfectly timed with someone in the US getting infected.

"Shit, this is on OUR turf now!??! Better do something about it!"

This is not "only now coming to light"; it's just that you couldn't be bothered to read about it until it was spelled out in a Slashdot headline. People didn't start working on this last week. I'm not sure how fast you think medical research works.

Dear AC, if you under fourteen years old nor drunk/high right now, and at any point in your life ask yourself the following question: "Could it be possible that this makes no sense to me because I'm stupid?" Be safe in the knowledge that the answer to your quandary is a resounding "Oh my fucking God! YES!"

Either they ate animal meat that wasn't cooked properly or they went there primarily to have sex with people or animals who knows.

Yes, because those are the ONLY two ways that people come in contact with fluids from animals. Thank God butchering is such a tidy process, animals don't bleed after you shoot them while on the hunt, and that people handling animals never get bitten, because if any of those were things that actually happened we might need to consider the possibility that there are other ways people could get infected, and we wouldn't want to do that!

Well, you're being a stupid fucking troll, but try this for size : when transiting West African countries to/ from my work on an oil exploration rig, I overnight at a hotel onshore, each way. so, if the bar tender, or chef, or waiter, or the mid who cleans my room leaves the virus on some hard surface they're handling...

Got it now? Just because your only idea of life is about fucking sheep or boys doesn't mean that there aren't transmission routes beyond your tiny imagination.

The mortality rate of the current outbreak vs. past outbreaks is different. Some of that difference may be caused by micro-evolutionary changes in the virus during this outbreak. Some of it may be related to lessons learned in carrying for patients. Applying a historical average doesn't make sense here.

They known the mortality rate of ebola when untreated.They can find out the mortality rate effect when vaccinated.

It isn't that simple. The situation on the ground is changing rapidly over time, so current rates are worthless as a point of comparison.

Compared to many diseases with which we're familiar, Ebola is rather difficult to transmit, given that someone needs to be in contact with the bodily fluids of an infected individual. As such, infection rates among the population of medical staff are highly dependent on the conditions of the environment. A properly maintained quarantine with medical professionals engaging in best practices should basically have a 0% infection rate, whereas the sorts of conditions they're seeing in Africa right now will see significantly higher infection rates among the medical staff, but even those rates can vary significantly from facility to facility depending on the facility's resources, the level of training of the staff and their assistants, and how cooperative the patients are. As those infection rates change, so too do the mortality rates. Moreover, as I mentioned, those rates are likely changing over time as new practices are put into place, training is improved, resources are improved thanks to new funding, or changes occur in the cultural awareness of the patients.

Which is all to say, you need some way to account for the changes to the mortality rate that are occurring for reasons besides the vaccine. Comparing future mortality rates against past rates doesn't do that. All that does is tell us that something has changed, but it doesn't tell us what changed. You need a control group in the same environment going through the same changes, with the only difference being that the test group is vaccinated. Anything else, and we'll have no way to isolate the efficacy of the vaccine or its lack thereof from the other changes occurring in the environment that are also affecting the outcome.

As such, infection rates among the population of medical staff are highly dependent on the conditions of the environment.

True. Not a helpful point though.

A properly maintained quarantine with medical professionals engaging in best practices should basically have a 0% infection rate,

Are you hearing the reports about the Spanish infection case? Allegedly (and it is an allegation, but one that has not yet, to my knowledge, been denied by the authorities of the hospital involved) the nurses cleaning up after t

There is always the risk of the control group sharing some property that the test group lacks.

Sure, but for a sufficiently large, randomly selected group, we can rule that out as a likelihood. You typically don't need too many people before you can be statistically certain that they're essentially homogenous.

The ethical thing would be to use the past as a control group.

Ethical in what regard? Yes, it respects the right to live of the medical workers currently in the field by giving them what we think offers them the best opportunity to live, but it comes at the cost of engaging in shoddy science that could potentially mislead us into pushing out a vaccine that

Jindal said that, although he also brought up a quarantine instead of a ban. 'The Conservatives' have said no such thing. But explain to us how limiting airline flights from there to here will spread Ebola more rapidly in Africa.

And don't forget the first conservatives to speak out on Ebola. Well, they didn't speak, per se; they just quietly went over there and did everything they could to help, with a few of them getting it themselves.

"And don't forget the first conservatives to speak out on Ebola. Well, they didn't speak, per se; they just quietly went over there and did everything they could to help, with a few of them getting it themselves."why do you consider those people conservative? What does that action have to do with political affiliation?

Vaccines are preventative. Inoculating someone who is already infected does not work.

Tell that to all of the medical researchers working on so-called therapeutic vaccines. Yes, most vaccines with which we're familiar are preventative in nature, designed to immunize an individual in an effort to prevent a possible future infection, but they are by no means the only type of vaccine. For instance, there are currently no preventative vaccines for cancer (quick note: there are, of course, vaccines that can prevent various causes for cancer, such as HPV, but there are no vaccines that prevent can

While I am not a medical professional, someone out there could argue that a drug designed to prevent more of your healthy X cells from being infected is a vaccine, even if some of your existing X cells are already infected. Substitute white blood, red blood, brain, heart, bone, etc. for X depending on the disease.

Humans are not homogenous and not every cell of an infected person is infected. While such a drug should probably be called both a treatment and a vaccine, language evolves and if people start ca

Medical history shows that going for the sort-sighted option can result in huge catastrophes. The other issue, which everybody seems to forget, is side-effects. If the vaccine kills 1 in 100 that get it, is it still worthwhile? It may be, but only for some people. There are vaccines with possible side-effects so bad that they are given only to people with a high risk of getting infected.